Immunodeficiency (Veterinary) PDF

Immunodeficiency Dr Felix N. Toka, DVM, PhD, DSc, DACVM  Objectives Define immunodeficiency Define primary and secondary immunodeficiencies Describe possibilities of diagnosing immunodeficiency Describe the nature and possible causes of congenital immunodeficiency De...

Immunodeficiency Dr Felix N. Toka, DVM, PhD, DSc, DACVM  Objectives Define immunodeficiency Define primary and secondary immunodeficiencies Describe possibilities of diagnosing immunodeficiency Describe the nature and possible causes of congenital immunodeficiency Describe the nature and possible causes of acquired immunodeficiency  What is immunodeficiency? It is a failure in humoral or cell-mediated limbs of the immune response If attributable to intrinsic defects in T and/or B lymphocytes, the condition is termed a primary immunodeficiency/Congenital immunodeficiency If the defect results from loss of function of antibody and or lymphocytes, the condition is a secondary immunodeficiency/acquired immunodeficiency The term may refer also to defective leukocytes or the complement system  Primary immunodeficiency A result of genetic defect(s) in one or more components of the immune system Stages of immune cell development at which genetic defects may occur leading to primary immunodeficiency 1. Failure of differentiation of the pluripotent stem cell 2. Failure of differentiation of the lymphoid/myeloid lineage from stem cells 3. Failure of T cell development 4. Failure of B cell development 5. Blockade of B cell differentiation into plasma cells 6. Failure of plasma cells to produce selected classes of Ig 7. Failure to produce functional neutrophils and macrophages 8. Failure to produce one or more complement components Stages of immune cell development at which genetic defects may occur leading to primary immunodeficiency When should primary immunodeficiency be suspected? Chronic or recurrent infections occur in relatively young animals Failure to respond to antibiotic or standard chemotherapy Multiple site infection occurs in young animals or littermates Infection with atypical microorganisms (e.g., saprophytes or commensals)  Lack of response to vaccine antigens Persistent leukocytosis or hypergammaglobulinemia Persistent leukopenia or hypogammaglobulinemia Allergy or concurrent autoimmune disease  Diagnosis of primary immunodeficiency The goal is to localize the immunological defect to one or more components of the immune system Ideally, the animals should be examined using a full panel of tests targeting the cell-mediated and humoral immunity  Possibilities of diagnostic procedures Hematology profile Bone marrow and lymph node biopsy Determination of complement component concentration in serum Screening for infectious diseases using the available serological and molecular techniques Full necropsy of dead littermates  Diagnostic procedures cont’d Determination of Ab response to vaccine antigens Immunophenotyping of lymphocytes in peripheral blood, particularly determination of the CD4+:CD8+ ratio (usually more CD4s than CD8s) Functional testing for neutrophils and macrophages Assessment of delayed type hypersensitivity (Type IV) using mitogens such as phytohemagglutinin (PHA) injected subcutaneously Atypical results should be confirmed at least twice Genetic testing is now available for some animal diseases e.g., Severe Combined Immune-deficiency (X-Linked SCID)  Immunodeficiencies associated with innate immunity May involve defects at various stages of phagocytosis Deficiencies in function of the complement system Dysfunction of NK cells  Chédiak-Higashi Syndrome, CHS Found in mink, persian cats, white tigers, cattle (Hereford, Japanese black cattle), horses, mice, orkas and humans Cause – mutation in the lyst (CHS1) gene. The gene encodes a protein that regulates lysosomal membrane trafficking The mutation is a misense - replacement of AT with GC (histidine  arginine) Defect leads to formation large secretory lysosomes in neutrophils, monocytes, eosinophils and melanocytes and the presence of numerous large granules in these cells  CHS A B Granules may fuse, rapture and cause tissue damage leading to lesions such as cataracts in the eye Leukocytes have reduced chemotactic activity and exhibit reduced intracellular cytotoxicity Normal neutrophil CHS neutrophil Cytotoxic cells such as NK cells may prematurely release the granule contents leading to tissue damage  Clinical presentation of CHS Loss of skin colour and dilution of hair pigmentation http://www.vetnext.com Eye abnormalities including development of cataracts and photophobia Increased susceptibility to infections, particularly the upper respiratory tract due to reduced activity of neutrophils  Septicemia in neonates Tendency to bleed abnormally following simple surgery, hematomas at injection sites. Death from acute hemorrhage may occur Dysfunction of NK cells, neutrophils and cytotoxic T cells  susceptibility to infection Increased susceptibility to tumors in young animals  Diagnosis Stained blood smears reveal enlarged granules in neutrophils Molecular testing (humans) Treatment - symptomatic Neurolink.com https://medschool.co/tests/full-blood-count/neutrophils Canine Leukocyte Adhesion Deficiency, CLAD Lack of integrin CD11b/CD18 (Mac-1) Neutrophils do not react to chemotactic factors Cannot bind to endothelial cells of blood vessels – cannot extravasate  CLAD Clinical features Animals die due to severe infections (lymphadenopathy, impaired pus formation, delayed wound healing) Leukocytosis (>200 000/μl), neutrophilia and eosinophilia Lack of leukocyte migration to sites of inflammation Recurrent infections despite a high number of neutrophils Have abnormal blood clotting The defect is usually found in Irish Red or White Setters  Molecular mechanism of CLAD Single missense mutation at position 107 in the β chain of CD18 (integrin beta -2) – leads to replacement of cysteine with serine  incorrect protein is produced The mutation disrupts disulfide bonds within the CD18 molecule  alteration of the proteins structure and function CD11b (integrin alpha M, α chain) is not expressed because it requires binding of the β chain before expression on the cell surface Bovine Leukocyte Adhesion Deficiency, BLAD The disease is found in Holstein calves Clinical presentation is similar to CLAD Calves die between 2 and 7 months after birth  Stunted growth and usually develop amyloidosis (deposition of amyloid in various tissues) Large number of neutrophils in circulation but not in tissues Mutation in the gene encoding CD18 – replacement of Asp with Gly  Canine Cyclic Neutropenia mutation in AP3β1 gene – the gene product is responsible for normal trafficking of granular proteins (such as elastase) to cytoplasmic granules during certain stages in hematopoiesis. results in a cyclic arrest of maturation of myeloid progenitor cells in the bone marrow, hence compromised production of early myeloid cells.  Fluctuation in the number of neutrophils in peripheral blood Loss of neutrophils appears every 11-12 days and lasts for at least 3 days Neutrophil number may normalize or increase every 7 days The neutropenia disables normal inflammatory reaction which leads to recurrent bacterial and fungal infections  Neutrophils have reduced myeloperoxidase activity Autosomal recessive disease of Border Collies Appears after weaning Animals with defect have discoloration of hair (gray- silver) http://www.pennylanecollies.net Pathology associated with cyclic neutropenia Gastrointestinal disease Respiratory tract infections Bone diseases lymphadenitis bleeding – because platelet number also undergoes cyclic changes Rarely live up to 3 years Elevated Ig levels Recurrent infections Treatment is symptomatic – prolonged antibiotic therapy leads to amyloidosis Severe combined immunodeficiency disease SCID Inheritance of an autosomal recessive trait. The diagram shows the outcome of mating between two horses that are heterozygous for the SCID trait. 50% of the offspring will be heterozygotes i.e., carriers, 25% will be homozygous for the dominant allele and 25% will be homozygous recessive i.e., affected with SCID  Molecular basis of SCID in horses Defect in a multicomponent enzyme responsible for DNA recombination (DNA-dependent protein kinase catalytic subunit) DNA-PKcs Mutation removes 5 nucleotides in the gene coding region of DNA-PKcs leading to a loss of 967 aa in the protein DNA- PKcs As a result, there is no recombination of variable regions of TCR and BCR Lymphocytes cannot recognize antigens  A hereditary disease mostly seen in pure and part-bred Arabian horses Lack of sufficient T and B lymphocyte production – very low numbers in circulation Foals are born healthy, but health problems begin at 2 months of age  If foals receive sufficient Ab in colostrum and milk, they are protected in the first two months after birth Agammaglobulinemia develops at the end of passive Ab catabolism Foals live for 4 to 6 months – die from severe bacterial, viral and fungal infections (bronchopneumonia is a frequent disease)  SCID in horses No germinal centers, (GC) and periarterial lymphoid Sheath, (PALS) in spleen No GC and no cells in the paracortical area of lymph nodes The thymus is very small if at all present May have functional NK cells, neutrophils and monocytes  Diagnosis of SCID in horses is important because of animal value 3 factors should co-exist to confirm SCID in horses good Few circulating lymphocytes – below 1000/ul R Lack of IgM in serum before suckling (normal level of IgM 160 μg/ml) nD Histology typical for SCID - hypoplazia of primary and secondary lymphatic organs  SCID in dogs Autosomal recessive disease of Jack Russell terriers Leads to lymphopenia, agammaglobulinemia, aplazia of the thymus and lymphoid tissue Defect located in gene coding DNA-PKsc 1.1% frequency of carrier status  X-linked Severe Combined Immunodeficiency (X-SCID) Is an inherited disorder of the immune system that occurs exclusively in males A disease of bassets and corgis Lack of lymph nodes  Molecular basis Mutation in the gene encoding γ chain of the IL-2 receptor (IL-2R) The γ chain is also found in receptors for IL-4, IL-7, IL-9 and IL-15 (γc, Common γ chain) In Bassets Removal of 4 nucleotides causes shift of the remaining nucleotides such that a STOP codon is generated prematurely Only part of the protein is produced – non-functional In Corgis Insertion of cytosine in the gene encoding IL-2R γ chain, generates a STOP codon that produces a non-functional protein In both cases lymphocytes are not reactive in the presence of IL-2 or other cytokines requiring a γ chain containing receptor – no mature T lymphocytes  Disease appears at 6-8 weeks of age when maternal antibody levels decrease Characterized by frequent infections: canine distemper, parvovirus infections, Cryptosporidiosis, Staphylococcal infections Reduced number of lymphocytes -